Under certain conditions (presence of catecholamines, high calcium), a period of fast drive of cardiac tissues can induce repetitive activity ("overdrive excitation") both in vivo and in vitro. The events underlying overdrive excitation are incompletely understood. The aim of the proposed project is to investigate several facets of the problem in pacemaker tissues of the heart perfused in vitro. The membrane potentials will be recorded by means of a microelectrode technique, membrane currents by a voltage clamp, force by a force transducer and intracellular ion activity by means of ion-sensitive electrodes. The problems under investigation will include the following: The relationship of different catecholamines and different receptors to overdrive excitation; the influence of different factors on overdrive excitation; the relationship between overdrive suppression and overdrive excitation; the electrical events leading to overdrive excitation; the ions involved in overdrive excitation; the intracellular activity of calcium and sodium when overdrive excitation occurs; overdrive excitation of slow responses; the characteristics of the current underlying overdrive excitation; the ionic nature of such current; the mode of action of antiarrhythmic agents in suppressing overdrive excitation. Some of these experiments will be conducted also in muscle tissues and in vivo. The different questions will be studied using the appropriate techniques which have been in use in this laboratory and by different experimental manipulations based on current knowledge. The results of different experiments will be correlated to provide integrated information about the cellular events which lead to the onset of repetitive activity following a period of overdrive. These experiments should provide information which may be relevant to some of the arrhythmias induced clinically by pacing the heart or occurring spontaneously.